Tolerability and efficacy of two synergistic ratios of oral morphine and oxycodone combinations versus morphine in patients with chronic noncancer pain.

OBJECTIVES: Analgesic synergy and improved tolerability have been reported for flexible dose morphine and oxycodone combinations. This report describes two studies with similar double-blind, randomized, 7-day crossover designs (up to 7 days per arm) conducted to 1) explore the analgesic and safety benefit offixed ratio of morphine (M) and oxycodone (0) combinations (MOX) and 2) define the optimal ratio for morphine and oxycodone combination. SETTING: Clinical study centers in Australia. PATIENTS: Patients with chronic noncancer pain. INTERVENTION: Eligible patients were randomly assigned to receive flexible doses of either M or fixed ratio of MOX (M3:02 in study A; M1:02 in study B). The starting doses of M or MOX were the morphine equivalent doses (MEDs) converted from the analgesics received before entering double-blind treatment. At each crossover period, the doses were titrated to achieve analgesia at steady state, which was defined as when the same total daily dose (+/-10 percent) had been given consecutively for 3 days. MAIN OUTCOME MEASURE: The primary endpoint was the study medication dose (MED), which produced adequate pain control at steady state. RESULTS: Analgesic synergy in MOX was observed in both studies. On an MED basis, 61.6 percent (study A, M:0 = 3:2) or 46.8 percent (study B, M:0 = 1:2) more MED were needed forM monotherapy to achieve steady-state pain control when compared with MOX. Patient tolerability profiles were also generally better in the MOX groups. CONCLUSION: A 3:2 or 1:2 fixed ratio combination of morphine and oxycodone (MOX) produced analgesic synergy and a tolerability profile improvement in patients with chronic noncancer pain.

Phospholipid-stabilized nanoparticles of cyclosporine A by rapid expansion from supercritical to aqueous solution.

The purpose of this research was to form stable suspensions of submicron particles of cyclosporine A, a water-insoluble drug, by rapid expansion from supercritical to aqueous solution (RESAS). A solution of cyclosporine A in CO2 was expanded into an aqueous solution containing phospholipid vesicles mixed with nonionic surfactants to provide stabilization against particle growth resulting from collisions in the expanding jet. The products were evaluated by measuring drug loading with high performance liquid chromatography (HPLC), particle sizing by dynamic light scattering (DLS), and particle morphology by transmission electron microscopy (TEM) and x-ray diffraction. The ability of the surfactant molecules to orient at the surface of the particles and provide steric stabilization could be manipulated by changing process variables including temperature and suspension concentration. Suspensions with high payloads (up to 54 mg/mL) could be achieved with a mean diameter of 500 nm and particle size distribution ranging from 40 to 920 nm. This size range is several hundred nanometers smaller than that produced by RESAS for particles stabilized by Tween 80 alone. The high drug payloads (approximately 10 times greater than the equilibrium solubility), the small particle sizes, and the long-term stability make this process attractive for development.